Viable, chronically dysfunctional myocardium progresses from chronically stunned (with normal resting flow) to hibernating myocardium (with reduced resting flow) as the physiological significance of a coronary stenosis supplying a dysfunctional region increases to the point that subendocardial vasodilator reserve is exhausted. At the cell and molecular level, the transition to hibernating myocardium is accompanied by a regional downregulation of sarcoplasmic reticulum calcium uptake proteins, apoptosis-induced myocyte loss with myocyte hypertrophy, and an attenuated contractile response to beta-adrenergic stimulation in the absence of infarction. Although contractile reserve is attenuated, hibernating myocardium is surprisingly protected against the development of metabolic evidence of ischemia. Based upon these findings our central hypothesis is that hibernating myocardium represents an adaptive myocardial response that arises from synergistic mechanisms acting to minimize a regional metabolic imbalance between a limited regional oxygen supply and demand. These adaptations serve to limit metabolic evidence of ischemia and minimize superimposed acute myocardial stunning. We will test this by completing four specific aims. Aim l will determine whether contractile function and metabolism differ following sudden vs. gradual increases in myocardial oxygen consumption and define whether the blunted metabolic response of hibernating myocardium is related to flow limitation or an intrinsic property of the myocardium. Aim 2 will determine whether hibernating myocardium is endogenously preconditioned against acute myocardial stunning produced by demand-induced ischemia via chronic induction of iNOS and determine whether it can be blocked by selectively inhibiting COX-2 or the mitochondrial K+ATP channel. Aim 3 will determine if repetitive episodes of ischemia lead to regional reductions in presynaptic neuronal norepinephrine uptake that contribute to the transition from chronically stunned to hibernating myocardium. Aim 4 will determine whether chronic alterations in beta-adrenergic receptor function and adenylyl cyclase activity are responsible for the blunted contractile response characteristic of hibernating myocardium. The results of the study are likely to lead to novel information that will improve our mechanistic understanding of chronic adaptations to myocardial ischemia and the physiological and biochemical factors responsible for modulating contractile reserve in the setting of a chronic coronary stenosis. [unreadable] [unreadable]